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Maximizing cancer synthetic lethality using dual PI-3K/PARP inhibitors

Award Number: R41CA206859
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2016
PERIOD OF PERFORMANCE END DATE: 12/19/2017

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Maximizing cancer synthetic lethality using dual PI-3K/PARP inhibitors - PARP inhibitors (PARPi) are particularly efficacious in tumors deficient in the BRCA1/2 tumor suppressor genes but of limited activity in BRCA competent tumors. There is an unmet medical need to develop targeted therapeutic agents which will augment PARPi activity for BRCA1/2 wild type cancers and to increase chemo- radiosensitivity in these malignancies. BRCA1/2 proteins are essential components of the homologous recombination (HR) double-strand DNA repair mechanism. PARPi's synthetic lethality derives from preventing the HR DNA double-strand break (DSB) repair mechanism which the cancer cell cannot overcome resulting in lethal DNA damage. PARPi are selectively toxic to cells with BRCA1/2 deficiencies or other DNA repair pathway mutations as found in some triple negative breast cancers. A recent report demonstrated that PI-3 kinase (PI-3K) inhibition impairs BRCA1/2 expression and can sensitize BRCA-proficient cancers to PARP inhibition. Hence, our central hypothesis to be tested in this proposal is that a combination dual PI-3K inhibitors (PI-3Ki)/ PARP inhibitor will attack the cancer cell’s DNA repair mechanisms via at least two orthogonal pathways and extend PARPi clinical activity beyond just those deficient in BRCA1/2 and/or other DNA repair defects. An innovative component of our proposal is that we have developed in silico the first small-molecule inhibitory chemotype which inhibits both PI-3K and PARP activity simultaneously (e.g. SRX3128; preliminary results). We have demonstrated “proof of concept” that SRX3128: 1) augments cell death following DNA damage 2) Inhibits both targets DNA repair and PI-3K simultaneously in the same tumor cell and 3) displays less toxicity in normal cells compared with individual inhibitory chemotypes at equivalent potency against targets. The significance of our proposal lies in our capacity to provide an optimizable promising single anticancer agent which will potently inhibit DNA repair via multiple orthogonal mechanisms and chemo-radiosensitive tumor cells to DNA damaging agents. This proposal will evaluate this approach by achieving the following aims setting the stage for phase II efforts to optimize the expected dual inhibitor lead compound(s) to a clinical candidate: Aim (Task) #1. Develop a dual PI-3 kinase/PARP inhibitor. Aim (Task) #2. Develop a predictive computational PARP model for the in silico docking of designed compounds. Approach: Improve in silico PARP-ligand fit parameters of our PARP model until a high PARP-docking/PARP- assay-inhibition correlation is achieved. Aim (Task) #3. Determine therapeutic window for dual PI-3K/PARP inhibition. Approach: Compare toxicity towards neuronal cancer stem cells versus normal neuronal stem cells (NSCs) when exposed to single PARP inhibitor or PI-3K inhibitor versus dual PARP/PI-3K inhibition conditions. The significance of this research is it will greatly expand the reach of PARP inhibition into BRCA-proficient cancers. This innovative approach attacks cancer using two distinct proven mechanisms with a single compound challenging the one-drug one-target dogma.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	SIGNALRX PHARMACEUTICALS, INC.	12545 EL CAMINO REAL	SAN DIEGO	CA	92130	SAN DIEGO	USA	Cancer Biology Research	000	1	5/1/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $299,738 )
2016	2016	SIGNALRX PHARMACEUTICALS, INC.	12545 EL CAMINO REAL	SAN DIEGO	CA	92130	SAN DIEGO	USA	Cancer Biology Research	000	1	9/22/2016	NEW	$299,738
														Subtotal = $299,738

Grand Total All Awards = $299,738

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Maximizing cancer synthetic lethality using dual PI-3K/PARP inhibitors

Award Number: R41CA206859

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/22/2016

PERIOD OF PERFORMANCE END DATE: 12/19/2017

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